Controversial Treatment Strategies in Oncology Pharmacy Practice
Controversial Treatment Strategies in Oncology Pharmacy Practice
Intraperitoneal vs Intravenous Chemotherapy in Ovarian Cancer
The role of intraperitoneal chemotherapy for ovarian cancer has become a controversial issue in oncology pharmacy practice. At the recent annual meeting of the American College of Clinical Pharmacy, held October 26-29, 2006, in St. Louis, Missouri, a focus session was held to provide a forum for discussion and debate on this topic and 2 others: the superiority of weight-based vs fixed dosing of chemotherapeutic agents, and a best dosing approach for carboplatin. Although all 3 treatment strategies have been embraced by many practitioners, each is associated with limitations that preclude benefit to all recipients, thus prompting this reexamination of their application in the clinical setting.
The incorporation of intraperitoneal (IP) chemotherapy as a standard of care for patients with optimally debulked, stage III ovarian cancer was discussed by Patrick T. Wong, PharmD, BCPS, Assistant Clinical Professor, University of California San Francisco School of Pharmacy, and Judith A. Smith, PharmD, FCCP, BCOP, Assistant Professor, University of Texas, MD Anderson Cancer Center, Houston, Texas.
The controversy over IP chemotherapy was refueled recently when the National Cancer Institute (NCI) issued a statement endorsing the administration of IP cisplatin in combination with intravenous (IV) or IP taxane to women with optimally debulked FIGO stage III ovarian cancer. The release of this statement coincided with the publication of findings from a randomized, phase 3 trial that compared IV paclitaxel plus cisplatin with IV paclitaxel plus IP cisplatin and IP paclitaxel in 415 women with stage III ovarian cancer.
Despite theoretical advantages of IP administration, such as improved drug delivery to and distribution within the IP cavity, its true benefit is unknown, Dr. Wong said. The current National Comprehensive Cancer Center guidelines state that IP chemotherapy can be considered as an option for low-volume, optimally debulked, stage III disease (category 2B).
According to a recent meta-analysis of 8 randomized trials that included 1819 women, participants who received IP chemotherapy were less likely to die (HR = 0.79, 95% CI: 0.70-0.90), and their disease-free interval was significantly prolonged (HR = 0.79, 95% CI: 0.69-0.90). Although IP chemotherapy was associated with less ototoxicity compared with the IV route, serious gastrointestinal effects, pain, and fever were more frequent with the IP route. Much of the data for this analysis was derived from 3 key clinical trials (Table).
In the trial by Alberts and colleagues, 546 eligible women with stage III ovarian cancer with ≤ 2 cm of residual disease were randomized to receive the same dose of cisplatin (100 mg/m) either by IP or IV route. Neuromuscular toxic effects, moderate to severe tinnitus, and clinical hearing loss were more frequent with IV cisplatin. Despite a survival benefit that favored IP cisplatin, reports of the activity of paclitaxel spread, and paclitaxel quickly became the accepted standard treatment. Paclitaxel was incorporated into other large studies evaluating IP chemotherapy, but the types and doses of IP and IV chemotherapy differed. In addition, the definition of residual disease, an important factor for patient success, differed among trials.
In the study by Markman and colleagues, gastrointestinal, hematologic, and metabolic toxicities were greater in the IP-treated group, and although their progression-free survival was superior, improvement in overall survival with this regimen was of borderline statistical significance.
In the trial that prompted the NCI statement, gastrointestinal, hematologic, neurologic, and metabolic toxicities in the IP treatment arm were greater; in fact, fewer than half of the patients were able to complete 6 courses of treatment. Despite this, median survival was extended by about 16 months in the IP group. Furthermore, while quality of life was significantly worse with IP treatment during the trial, it was not different between IV and IP treatment groups at 1 year.
Patient selection is critical, Dr. Smith emphasized, and if IP chemotherapy is to be used, practitioners are urged to follow the protocol described. They should also consider the fact that IP drug administration requires inpatient care, which is a major inconvenience for many patients. Meanwhile, several issues remain unresolved, she said, such as the question of whether it is the route, the dose, or the schedule of chemotherapy that has accounted for differences in outcome, as well as the question of whether there are better ways to manage toxicity with IP chemotherapy.
Dr. Wong presented several tips to improve tolerability of intraperitoneally administered chemotherapy.
Table. Important Clinical Trials Investigating Intraperitoneal Chemotherapy in Ovarian Cancer
Weight-based vs Fixed Dosing for Chemotherapy Agents
Should chemotherapy doses be calculated on the basis of an individual's body surface area (BSA) or administered as fixed doses? That question was addressed by Scott Soefje, PharmD, BCOP, Regional Medical Liaison-Oncology, Amgen, Inc, San Antonio, Texas, and Paul R. Hutson, PharmD, Associate Professor, University of Wisconsin, Madison. Despite a long history of drug development and clinical administration of anticancer drug doses based on BSA, a growing body of literature provides evidence to challenge this approach.
The BSA formula was developed by DuBois as a way to normalize basal metabolic rate among individuals. This method has been used since the 1950s to extrapolate from the doses of anticancer agents given to experimental animals in order to determine safe starting doses for phase 1 studies with human subjects. For decades, doses of anticancer agents have been "individualized" according to patients' BSA, with the belief that this approach reduces variability among individuals in terms of drug exposure and effects. However, BSA-based dosing significantly reduces total variability in drug clearance for only a small number of drugs. Dr. Soefje provided several arguments against BSA dosing, including issues regarding its accuracy, inconsistencies in practitioners' diligence in verifying patients' heights, and the absence of strong correlations between BSA and several key physiologic parameters. For many agents, BSA-normalized dosing has proven no more accurate than flat fixed-dosing strategies.
Baker and colleagues conducted a retrospective assessment of the pharmacokinetics of investigational agents tested in phase 1 trials over a 10-year period as a function of BSA. Data obtained from 1650 patients were used to determine values for drug clearance and interindividual variation in drug clearance. Of the 33 agents tested, interindividual variability was significantly reduced using BSA-based dosing for only 5 agents: fluorouracil/eniluracil, paclitaxel, temozolomide, troxacitabine, and docosahexaenoic acid (DHA).These findings suggest that BSA-based dose calculations should not be used to determine starting doses of investigational agents for phase 1 trials.
A prospective study examined the usefulness of fixed- or BSA-based dosing of cisplatin on interindividual variability in drug exposure in 25 patients at extremes of BSA values. Data from a population of patients with normal-range BSA values were retrospectively analyzed for comparison. Compared with the average, unbound platinum clearance in patients with BSA less than 1.65 m was slower (P < .001), whereas clearance was faster in those individuals with BSA greater than 2.05 m (P < .001). These findings support the use of fixed dose recommendations of cisplatin based on clusters of BSA values (eg, ≤1.65 m; 1.66 m to 2.04 m; ≥ 2.05 m).
A prospective comparison of a flat-fixed and a BSA-normalized dose showed no differences in interindividual variability in irinotecan clearance, conversion to SN-38, or extent of SN-38 glucuronidation. Irinotecan-related hematologic side effects were also similar between groups. Thus, a flat fixed-dosing strategy for irinotecan could provide a safe alternative to current BSA-based dose calculations.
Dr. Soefje proposed several advantages of flat fixed dosing compared with BSA-based dosing calculations for anticancer agents:
While acknowledging the simplicity of this approach, Dr. Hutson suggested that the need to stock multiple vials of "fixed" doses of agents could, in fact, increase the potential for medication errors and may not be more economical. He noted that there is a scientific rationale for weight-based dosing, and he reviewed relationships between drug clearance and steady-state volume of distribution to weight. Furthermore, dose normalization using BSA has been shown to decrease apparent interindividual variability for some agents, he said. For example, both total and unbound paclitaxel clearance were significantly related to BSA, weight, and body mass. BSA-based dosing reduced interindividual variability of unbound paclitaxel area under the plasma concentration vs time curve (AUC) by 53.3%. These results provide a pharmacokinetic rationale for BSA-based dose calculations for paclitaxel.
In situations where clearance correlates poorly with BSA or weight, certain confounding covariates may be relevant, such as detoxifying enzyme inhibition or induction, efflux pump induction or inhibition, or renal dysfunction. To determine this appropriately, one would need to address all covariates that might influence variability in drug disposition and/or response. When possible, pharmacokinetic assessments should continue through all phases of clinical trials, along with collection of information of known covariates of drug distribution and elimination, molecular determinants of tumor biology, and patient outcomes for multivariate pharmacokinetic/pharmacodynamic analysis. Dr. Hutson mentioned, however, that "we need a reality check" to keep this in perspective. Although weight or BSA might account for up to a 2-fold variability in drug exposure, other factors such as renal filtration and protein binding or differences in drug metabolism, receptor expression, and transporter pumps are associated with potential variability of 10- to 1000-fold.
Carboplatin Dosing: Actual Parameters vs Adjusted or Assigned Parameters
Carboplatin dosing methods were the focus of a discussion by Hai T. Tran, PharmD, Assistant Professor, University of Texas MD Anderson Cancer Center, Houston, Texas, and Jon D. Herrington, PharmD, BCPS, BCOP, Hematology/Oncology Clinical Specialist, Scott & White Memorial Hospital, and Assistant Professor of Medicine, Texas A&M University College of Medicine, Temple, Texas. Carboplatin is excreted primarily by the kidneys, with about 65% to 70% of the total platinum dose eliminated in the urine as intact drug 12-16 hours after administration.
The primary dose-limiting toxicity of carboplatin is myelosuppression, and the severity of both thrombocytopenia and leukopenia has been related to carboplatin exposure, expressed as AUC. Moreover, therapeutic outcomes for various malignancies have been associated with carboplatin AUC. Carboplatin clearance is linearly related to glomerular filtration rate (GFR) and, as such, equations have been proposed to calculate an appropriate carboplatin dose to achieve a target AUC in an individual patient with a known GFR. Each equation has been associated with some degree of bias, which can be influenced by renal function, body weight, and other patient characteristics.
Egorin and colleagues presented an early model for dosing carboplatin that incorporated values for renal function, BSA, and desired level of thrombocytopenia. A second model, commonly referred to as the Calvert equation, was developed through a 3-stage process, whereby a carboplatin dose can be calculated on the basis of a target AUC and an estimated GFR:
Dose (mg) = Target AUC (mg/mL/min) x [GFR (mL/min) + 25]
Dr. Tran explained how some bias was introduced into this equation through the rounding of parameters derived from the data during the first 2 stages. Furthermore, the model was developed using CR-EDTA as a measure of GFR, which is impractical in the clinical setting. As a result, when an estimated creatinine clearance (calculated using either the Cockcroft-Gault or Jelliffe equations) is substituted for GFR, both overpredict the GFR for patients with low creatinine clearances and underpredict the GFR for patients with high creatinine clearances. An alternative approach, the "Chatelut formula," incorporates relationships between carboplatin clearance with age, weight, sex, and serum creatinine, and permits direct estimation of carboplatin clearance.
Donahue and colleagues compared estimations of carboplatin clearance using 4 different GFR determinations and the Chatelut formula. The Chatelut formula and Cockcroft-Gault formulas performed equally well in calculating carboplatin clearance. Estimates of carboplatin clearance using the Cockcroft-Gault formula, 2-hour urine collection, or 24-hour urine collection were associated with greater negative bias and are more likely to result in underdosing of carboplatin. In a separate trial, all formulas except for the Jelliffe equation predicted carboplatin clearance well.
Nonetheless, Dr. Tran suggests that clinicians pick a formula, monitor patient outcomes, and individualize dosing. He suggests that this is "as good as it gets," and that "good is good enough." One resource that clinicians may find useful is a carboplatin dosage calculator on the Free Pharmacokinetics Web site. Both the Calvert and Chatelut formulas can be used, but be cautious, because data entry mistakes will not be identified and could lead to dosing errors.
In his discussion of adjusted and assigned parameters used to calculate carboplatin doses, Dr. Herrington provided examples of how doses might differ according to whether unadjusted, adjusted, or ideal body weight-adjusted creatinine clearance estimates were used. Hutson and colleagues have provided guidelines for selecting an appropriate weight value, but these are equation-specific.
In his study, Dr. Herrington compared the target carboplatin AUC with the actual carboplatin AUC in overweight, obese, and cachectic patients. In patients with body mass index (BMI) ≥ 27, the carboplatin dose was calculated using the Cockcroft-Gault equation and adjusted body weight. Carboplatin AUC was measured, and these findings were compared to estimates based on a modified Cockcroft-Gault equation for the Calvert, Chatelut, and Bénézet formulas. Carboplatin pharmacokinetic parameters were similar between patient groups.
The modified Cockcroft-Gault equation for the Calvert formula was found to be the least biased and most precise. The use of adjusted body weight or ideal body weight was more accurate for patients with BMI ≥ 30. The use of actual weight in overweight and obese patients, as well as serum creatinine values below 70.7 micrometers in patients with cachexia, will lead to overestimation of carboplatin clearance and should be avoided. Also, the method used to analyze serum creatinine should be considered, since this can impact final carboplatin dose estimates.
Summary
The question of whether IP chemotherapy should be considered standard of care for patients with optimally debulked, stage III ovarian cancer remains controversial, but findings from the randomized trial published earlier this year demonstrate that women who are able to receive this regimen may experience a significant survival benefit. Appropriate patient selection is critical, and strategies to reduce treatment tolerability are imperative.
It remains unlikely that BSA-based or flat fixed-dose determinations will be appropriate for all chemotherapeutic agents, and different approaches may be necessary for specific agents. For those agents for which BSA-based dosing has not been shown to reduce interindividual variability, flat fixed doses should be considered, followed by dosage adjustments based on toxicities. Efforts should be made to identify alternative dosing strategies where BSA dose normalization does not modify interindividual variability.
When using a particular method to estimate creatinine clearance and/or carboplatin clearance in order to determine an appropriate carboplatin dose, any limitations of the particular equation should be considered. Patient-specific parameters, such as weight, serum creatinine, sex, renal function, and age, may influence the bias and precision of these estimates. Despite these limitations, current approaches that estimate carboplatin doses on the basis of target AUC values are better than approaches based on dosing carboplatin by BSA.
References
The role of intraperitoneal chemotherapy for ovarian cancer has become a controversial issue in oncology pharmacy practice. At the recent annual meeting of the American College of Clinical Pharmacy, held October 26-29, 2006, in St. Louis, Missouri, a focus session was held to provide a forum for discussion and debate on this topic and 2 others: the superiority of weight-based vs fixed dosing of chemotherapeutic agents, and a best dosing approach for carboplatin. Although all 3 treatment strategies have been embraced by many practitioners, each is associated with limitations that preclude benefit to all recipients, thus prompting this reexamination of their application in the clinical setting.
The incorporation of intraperitoneal (IP) chemotherapy as a standard of care for patients with optimally debulked, stage III ovarian cancer was discussed by Patrick T. Wong, PharmD, BCPS, Assistant Clinical Professor, University of California San Francisco School of Pharmacy, and Judith A. Smith, PharmD, FCCP, BCOP, Assistant Professor, University of Texas, MD Anderson Cancer Center, Houston, Texas.
The controversy over IP chemotherapy was refueled recently when the National Cancer Institute (NCI) issued a statement endorsing the administration of IP cisplatin in combination with intravenous (IV) or IP taxane to women with optimally debulked FIGO stage III ovarian cancer. The release of this statement coincided with the publication of findings from a randomized, phase 3 trial that compared IV paclitaxel plus cisplatin with IV paclitaxel plus IP cisplatin and IP paclitaxel in 415 women with stage III ovarian cancer.
Despite theoretical advantages of IP administration, such as improved drug delivery to and distribution within the IP cavity, its true benefit is unknown, Dr. Wong said. The current National Comprehensive Cancer Center guidelines state that IP chemotherapy can be considered as an option for low-volume, optimally debulked, stage III disease (category 2B).
According to a recent meta-analysis of 8 randomized trials that included 1819 women, participants who received IP chemotherapy were less likely to die (HR = 0.79, 95% CI: 0.70-0.90), and their disease-free interval was significantly prolonged (HR = 0.79, 95% CI: 0.69-0.90). Although IP chemotherapy was associated with less ototoxicity compared with the IV route, serious gastrointestinal effects, pain, and fever were more frequent with the IP route. Much of the data for this analysis was derived from 3 key clinical trials (Table).
In the trial by Alberts and colleagues, 546 eligible women with stage III ovarian cancer with ≤ 2 cm of residual disease were randomized to receive the same dose of cisplatin (100 mg/m) either by IP or IV route. Neuromuscular toxic effects, moderate to severe tinnitus, and clinical hearing loss were more frequent with IV cisplatin. Despite a survival benefit that favored IP cisplatin, reports of the activity of paclitaxel spread, and paclitaxel quickly became the accepted standard treatment. Paclitaxel was incorporated into other large studies evaluating IP chemotherapy, but the types and doses of IP and IV chemotherapy differed. In addition, the definition of residual disease, an important factor for patient success, differed among trials.
In the study by Markman and colleagues, gastrointestinal, hematologic, and metabolic toxicities were greater in the IP-treated group, and although their progression-free survival was superior, improvement in overall survival with this regimen was of borderline statistical significance.
In the trial that prompted the NCI statement, gastrointestinal, hematologic, neurologic, and metabolic toxicities in the IP treatment arm were greater; in fact, fewer than half of the patients were able to complete 6 courses of treatment. Despite this, median survival was extended by about 16 months in the IP group. Furthermore, while quality of life was significantly worse with IP treatment during the trial, it was not different between IV and IP treatment groups at 1 year.
Patient selection is critical, Dr. Smith emphasized, and if IP chemotherapy is to be used, practitioners are urged to follow the protocol described. They should also consider the fact that IP drug administration requires inpatient care, which is a major inconvenience for many patients. Meanwhile, several issues remain unresolved, she said, such as the question of whether it is the route, the dose, or the schedule of chemotherapy that has accounted for differences in outcome, as well as the question of whether there are better ways to manage toxicity with IP chemotherapy.
Dr. Wong presented several tips to improve tolerability of intraperitoneally administered chemotherapy.
Table. Important Clinical Trials Investigating Intraperitoneal Chemotherapy in Ovarian Cancer
| Authors | Population | Treatment Arms | Results |
|---|---|---|---|
| Alberts et al | Stage III, ≤ 2 cm residual disease | *Cyclophosphamide 600 mg/m IV plus cisplatin 100 mg/m IV*Cyclophosphamide 600 mg/m IV plus cisplatin 100 mg/m IP | Median survival longer with IP cisplatin (49 mos; 95% CI 42-56) vs IV cisplatin (41 months; 95% CI 34-47); IP cisplatin associated with lower risk of death (HR = 0.76, P = .02) |
| Markman et al | Stage III, ≤ 1 cm residual disease | *Paclitaxel 135 mg/m plus cisplatin 75 mg/m IV*Carboplatin (AUC 9) IV, then paclitaxel 135 mg/m IV plus cisplatin 100 mg/m IP | Median progression-free survival longer with IP cisplatin (28 vs 22 months; RR 0.78, P = .01), with trend for improved overall survival (63 vs 52 months; RR 0.81, P = .05) |
| Armstrong et al | Stage III, ≤ 1 cm residual disease | *Paclitaxel 135 mg/m IV plus cisplatin 75 mg/m IV*Paclitaxel 135 mg/m IV plus cisplatin 100 mg/m IP, then paclitaxel 60 mg/m IP | Median progression-free survival with IV vs IV therapy was 18.3 and 23.8 months, P = .05; median overall survival 49.7 and 65.5 months with IV and IP therapy, P = .03 |
Should chemotherapy doses be calculated on the basis of an individual's body surface area (BSA) or administered as fixed doses? That question was addressed by Scott Soefje, PharmD, BCOP, Regional Medical Liaison-Oncology, Amgen, Inc, San Antonio, Texas, and Paul R. Hutson, PharmD, Associate Professor, University of Wisconsin, Madison. Despite a long history of drug development and clinical administration of anticancer drug doses based on BSA, a growing body of literature provides evidence to challenge this approach.
The BSA formula was developed by DuBois as a way to normalize basal metabolic rate among individuals. This method has been used since the 1950s to extrapolate from the doses of anticancer agents given to experimental animals in order to determine safe starting doses for phase 1 studies with human subjects. For decades, doses of anticancer agents have been "individualized" according to patients' BSA, with the belief that this approach reduces variability among individuals in terms of drug exposure and effects. However, BSA-based dosing significantly reduces total variability in drug clearance for only a small number of drugs. Dr. Soefje provided several arguments against BSA dosing, including issues regarding its accuracy, inconsistencies in practitioners' diligence in verifying patients' heights, and the absence of strong correlations between BSA and several key physiologic parameters. For many agents, BSA-normalized dosing has proven no more accurate than flat fixed-dosing strategies.
Baker and colleagues conducted a retrospective assessment of the pharmacokinetics of investigational agents tested in phase 1 trials over a 10-year period as a function of BSA. Data obtained from 1650 patients were used to determine values for drug clearance and interindividual variation in drug clearance. Of the 33 agents tested, interindividual variability was significantly reduced using BSA-based dosing for only 5 agents: fluorouracil/eniluracil, paclitaxel, temozolomide, troxacitabine, and docosahexaenoic acid (DHA).These findings suggest that BSA-based dose calculations should not be used to determine starting doses of investigational agents for phase 1 trials.
A prospective study examined the usefulness of fixed- or BSA-based dosing of cisplatin on interindividual variability in drug exposure in 25 patients at extremes of BSA values. Data from a population of patients with normal-range BSA values were retrospectively analyzed for comparison. Compared with the average, unbound platinum clearance in patients with BSA less than 1.65 m was slower (P < .001), whereas clearance was faster in those individuals with BSA greater than 2.05 m (P < .001). These findings support the use of fixed dose recommendations of cisplatin based on clusters of BSA values (eg, ≤1.65 m; 1.66 m to 2.04 m; ≥ 2.05 m).
A prospective comparison of a flat-fixed and a BSA-normalized dose showed no differences in interindividual variability in irinotecan clearance, conversion to SN-38, or extent of SN-38 glucuronidation. Irinotecan-related hematologic side effects were also similar between groups. Thus, a flat fixed-dosing strategy for irinotecan could provide a safe alternative to current BSA-based dose calculations.
Dr. Soefje proposed several advantages of flat fixed dosing compared with BSA-based dosing calculations for anticancer agents:
Simplicity;
Reduced potential for medication errors;
Allows for simplistic dosing changes;
Pharmacokinetic variability not different from that with BSA dosing;
Alternative until something better comes along; and
Cost-effective.
While acknowledging the simplicity of this approach, Dr. Hutson suggested that the need to stock multiple vials of "fixed" doses of agents could, in fact, increase the potential for medication errors and may not be more economical. He noted that there is a scientific rationale for weight-based dosing, and he reviewed relationships between drug clearance and steady-state volume of distribution to weight. Furthermore, dose normalization using BSA has been shown to decrease apparent interindividual variability for some agents, he said. For example, both total and unbound paclitaxel clearance were significantly related to BSA, weight, and body mass. BSA-based dosing reduced interindividual variability of unbound paclitaxel area under the plasma concentration vs time curve (AUC) by 53.3%. These results provide a pharmacokinetic rationale for BSA-based dose calculations for paclitaxel.
In situations where clearance correlates poorly with BSA or weight, certain confounding covariates may be relevant, such as detoxifying enzyme inhibition or induction, efflux pump induction or inhibition, or renal dysfunction. To determine this appropriately, one would need to address all covariates that might influence variability in drug disposition and/or response. When possible, pharmacokinetic assessments should continue through all phases of clinical trials, along with collection of information of known covariates of drug distribution and elimination, molecular determinants of tumor biology, and patient outcomes for multivariate pharmacokinetic/pharmacodynamic analysis. Dr. Hutson mentioned, however, that "we need a reality check" to keep this in perspective. Although weight or BSA might account for up to a 2-fold variability in drug exposure, other factors such as renal filtration and protein binding or differences in drug metabolism, receptor expression, and transporter pumps are associated with potential variability of 10- to 1000-fold.
Carboplatin Dosing: Actual Parameters vs Adjusted or Assigned Parameters
Carboplatin dosing methods were the focus of a discussion by Hai T. Tran, PharmD, Assistant Professor, University of Texas MD Anderson Cancer Center, Houston, Texas, and Jon D. Herrington, PharmD, BCPS, BCOP, Hematology/Oncology Clinical Specialist, Scott & White Memorial Hospital, and Assistant Professor of Medicine, Texas A&M University College of Medicine, Temple, Texas. Carboplatin is excreted primarily by the kidneys, with about 65% to 70% of the total platinum dose eliminated in the urine as intact drug 12-16 hours after administration.
The primary dose-limiting toxicity of carboplatin is myelosuppression, and the severity of both thrombocytopenia and leukopenia has been related to carboplatin exposure, expressed as AUC. Moreover, therapeutic outcomes for various malignancies have been associated with carboplatin AUC. Carboplatin clearance is linearly related to glomerular filtration rate (GFR) and, as such, equations have been proposed to calculate an appropriate carboplatin dose to achieve a target AUC in an individual patient with a known GFR. Each equation has been associated with some degree of bias, which can be influenced by renal function, body weight, and other patient characteristics.
Egorin and colleagues presented an early model for dosing carboplatin that incorporated values for renal function, BSA, and desired level of thrombocytopenia. A second model, commonly referred to as the Calvert equation, was developed through a 3-stage process, whereby a carboplatin dose can be calculated on the basis of a target AUC and an estimated GFR:
Dose (mg) = Target AUC (mg/mL/min) x [GFR (mL/min) + 25]
Dr. Tran explained how some bias was introduced into this equation through the rounding of parameters derived from the data during the first 2 stages. Furthermore, the model was developed using CR-EDTA as a measure of GFR, which is impractical in the clinical setting. As a result, when an estimated creatinine clearance (calculated using either the Cockcroft-Gault or Jelliffe equations) is substituted for GFR, both overpredict the GFR for patients with low creatinine clearances and underpredict the GFR for patients with high creatinine clearances. An alternative approach, the "Chatelut formula," incorporates relationships between carboplatin clearance with age, weight, sex, and serum creatinine, and permits direct estimation of carboplatin clearance.
Donahue and colleagues compared estimations of carboplatin clearance using 4 different GFR determinations and the Chatelut formula. The Chatelut formula and Cockcroft-Gault formulas performed equally well in calculating carboplatin clearance. Estimates of carboplatin clearance using the Cockcroft-Gault formula, 2-hour urine collection, or 24-hour urine collection were associated with greater negative bias and are more likely to result in underdosing of carboplatin. In a separate trial, all formulas except for the Jelliffe equation predicted carboplatin clearance well.
Nonetheless, Dr. Tran suggests that clinicians pick a formula, monitor patient outcomes, and individualize dosing. He suggests that this is "as good as it gets," and that "good is good enough." One resource that clinicians may find useful is a carboplatin dosage calculator on the Free Pharmacokinetics Web site. Both the Calvert and Chatelut formulas can be used, but be cautious, because data entry mistakes will not be identified and could lead to dosing errors.
In his discussion of adjusted and assigned parameters used to calculate carboplatin doses, Dr. Herrington provided examples of how doses might differ according to whether unadjusted, adjusted, or ideal body weight-adjusted creatinine clearance estimates were used. Hutson and colleagues have provided guidelines for selecting an appropriate weight value, but these are equation-specific.
In his study, Dr. Herrington compared the target carboplatin AUC with the actual carboplatin AUC in overweight, obese, and cachectic patients. In patients with body mass index (BMI) ≥ 27, the carboplatin dose was calculated using the Cockcroft-Gault equation and adjusted body weight. Carboplatin AUC was measured, and these findings were compared to estimates based on a modified Cockcroft-Gault equation for the Calvert, Chatelut, and Bénézet formulas. Carboplatin pharmacokinetic parameters were similar between patient groups.
The modified Cockcroft-Gault equation for the Calvert formula was found to be the least biased and most precise. The use of adjusted body weight or ideal body weight was more accurate for patients with BMI ≥ 30. The use of actual weight in overweight and obese patients, as well as serum creatinine values below 70.7 micrometers in patients with cachexia, will lead to overestimation of carboplatin clearance and should be avoided. Also, the method used to analyze serum creatinine should be considered, since this can impact final carboplatin dose estimates.
Summary
The question of whether IP chemotherapy should be considered standard of care for patients with optimally debulked, stage III ovarian cancer remains controversial, but findings from the randomized trial published earlier this year demonstrate that women who are able to receive this regimen may experience a significant survival benefit. Appropriate patient selection is critical, and strategies to reduce treatment tolerability are imperative.
It remains unlikely that BSA-based or flat fixed-dose determinations will be appropriate for all chemotherapeutic agents, and different approaches may be necessary for specific agents. For those agents for which BSA-based dosing has not been shown to reduce interindividual variability, flat fixed doses should be considered, followed by dosage adjustments based on toxicities. Efforts should be made to identify alternative dosing strategies where BSA dose normalization does not modify interindividual variability.
When using a particular method to estimate creatinine clearance and/or carboplatin clearance in order to determine an appropriate carboplatin dose, any limitations of the particular equation should be considered. Patient-specific parameters, such as weight, serum creatinine, sex, renal function, and age, may influence the bias and precision of these estimates. Despite these limitations, current approaches that estimate carboplatin doses on the basis of target AUC values are better than approaches based on dosing carboplatin by BSA.
References
Wong PT, Smith JA. Intraperitoneal vs. intravenous chemotherapy in ovarian cancer. Program of The American College of Clinical Pharmacy 2006 Annual Meeting; October 26-29, 2006; St. Louis, Missouri.
NCI Clinical Announcement. Intraperitoneal chemotherapy for ovarian cancer. January 5, 2006. Available at http://ctep.cancer.gov/highlights/clin_annc_010506.pdf. Accessed December 12, 2006.
Armstrong DK, Bundy B, Wenzel L. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354:34-43. Abstract
National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: ovarian cancer. Available at http://www.nccn.org/professionals/physician_gls/PDF/ovarian.pdf. Accessed December 12, 2006.
Jaaback K, Johnson N. Intraperitoneal chemotherapy for the initial management of primary epithelial ovarian cancer. Cochrane Database Syst Rev. 2006;1:CD005340.
Alberts DS, Liu PY, Hannigan EV, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med. 1996;335:1950-1955. Abstract
McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med. 1996;334:1-6. Abstract
Markman M, Bundy BN, Alberts DS, et al. Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol. 2001;19:1001-1007. Abstract
Markman M, Walker JL. Intraperitoneal chemotherapy of ovarian cancer: a review, with a focus on practical aspects of treatment. J Clin Oncol. 2006;24:988-94. Abstract
Soefje S, Hutson PR. Weight-based vs. fixed dosing for chemotherapy agents. Program of The American College of Clinical Pharmacy 2006 Annual Meeting; October 26-29, 2006; St. Louis, Missouri.
Felici A, Verweij J, Sparreboom A. Dosing strategies for anticancer drugs: the good, the bad and body-surface area. Eur J Cancer. 2002;38:1677-1684. Abstract
Baker SD, Verweij J, Rowinsky EK, et al. Role of body surface area in dosing of investigational anticancer agents in adults, 1991-2001. J Natl Cancer Inst. 2002;94:1883-1888. Abstract
Loos WJ, de Jongh FE, Sparreboom A, et al. Evaluation of an alternate dosing strategy for cisplatin in patients with extreme body surface area values. J Clin Oncol. 2006;24:1499-1506. Abstract
de Jong FA, Mathijssen RH, Xie R, et al. Flat-fixed dosing of irinotecan: influence on pharmacokinetic and pharmacodynamic variability. Clin Cancer Res. 2004;10:4068-4071. Abstract
Smorenburg CH, Sparreboom A, Bontenbal M, et al. Randomized cross-over evaluation of body-surface area-based dosing versus flat-fixed dosing of paclitaxel. J Clin Oncol. 2003;21:197-202. Abstract
Train HT, Herrington JD. Carboplatin dosing: actual parameters vs. adjusted or assigned parameters. Program of The American College of Clinical Pharmacy 2006 Annual Meeting; October 26-29, 2006; St. Louis, Missouri.
Alberts DS, Dorr RT. New perspectives on an old friend: optimizing carboplatin for the treatment of solid tumors. Oncologist. 1998;3:15-34. Abstract
Ekhart C, de Jonge ME, Huitema AD, et al. Flat dosing of carboplatin is justified in adult patients with normal renal function. Clin Cancer Res. 2006;12:6502-6508. Abstract
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